The influence of iron oxidation state on quantitative MRI parameters in post mortem human brain

Birkl, Christoph; Birkl-Toeglhofer, Anna Maria; Kames, Christian; Goessler, Walter; Haybaeck, Johannes; Fazekas, Franz; Ropele, Stefan; Rauscher, Alexander

doi:10.1016/j.neuroimage.2020.117080

Cited by 34 publications

(29 citation statements)

References 60 publications

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“…As oligodendrocytes are the major iron‐containing cells in the adult central nervous system (Connor & Menzies, 1995 ), the above studies also support the notion that changes in MTR observed in this study may be driven by iron alterations, and such a proposition is consistent with evidence that changes in iron affect magnetization transfer parameters (Birkl et al, 2020 ). Crucially, however, as iron and myelin levels in the brain are tightly related, these two explanations are not mutually exclusive, and further work is needed to uncover the generative mechanism underpinning the present findings.…”

Section: Discussionsupporting

confidence: 90%

Mutation‐related magnetization‐transfer, not axon density, drives white matter differences in premanifest Huntington disease: Evidence from in vivo ultra‐strong gradient MRI

Casella

Chamberland

Laguna

et al. 2022

Human Brain Mapping

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White matter (WM) alterations have been observed in Huntington disease (HD) but their role in the disease‐pathophysiology remains unknown. We assessed WM changes in premanifest HD by exploiting ultra‐strong‐gradient magnetic resonance imaging (MRI). This allowed to separately quantify magnetization transfer ratio (MTR) and hindered and restricted diffusion‐weighted signal fractions, and assess how they drove WM microstructure differences between patients and controls. We used tractometry to investigate region‐specific alterations across callosal segments with well‐characterized early‐ and late‐myelinating axon populations, while brain‐wise differences were explored with tract‐based cluster analysis (TBCA). Behavioral measures were included to explore disease‐associated brain‐function relationships. We detected lower MTR in patients' callosal rostrum (tractometry: p = .03; TBCA: p = .03), but higher MTR in their splenium (tractometry: p = .02). Importantly, patients' mutation‐size and MTR were positively correlated (all p ‐values < .01), indicating that MTR alterations may directly result from the mutation. Further, MTR was higher in younger, but lower in older patients relative to controls ( p = .003), suggesting that MTR increases are detrimental later in the disease. Finally, patients showed higher restricted diffusion signal fraction (FR) from the composite hindered and restricted model of diffusion (CHARMED) in the cortico‐spinal tract ( p = .03), which correlated positively with MTR in the posterior callosum ( p = .033), potentially reflecting compensatory mechanisms. In summary, this first comprehensive, ultra‐strong gradient MRI study in HD provides novel evidence of mutation‐driven MTR alterations at the premanifest disease stage which may reflect neurodevelopmental changes in iron, myelin, or a combination of these.

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Section: Discussionsupporting

confidence: 90%

Mutation‐related magnetization‐transfer, not axon density, drives white matter differences in premanifest Huntington disease: Evidence from in vivo ultra‐strong gradient MRI

Casella

Chamberland

Laguna

et al. 2022

Human Brain Mapping

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“…Several studies have shown that T 2 relaxation is also affected (shortened T 2 relaxation time, hypointensities on T 2 -weighted MRI) by iron accumulation [ 3 , 9 , 202 ]. In principle, MRI techniques are sensitive to local magnetic field variations caused by iron compounds that affect MR-relaxation parameters [ 203 ]. In the human brain, the following four main iron particles are found: hemoglobin-bound iron, which is present in the blood and which exhibits nearly paramagnetic behavior; magnetite- or maghemite-bound ion; iron bound to transferrin (the main iron transporter protein in the brain [ 204 , 205 ]) or ferroportin; and iron stores such as ferritin (the main intracellular iron storage protein in the brain [ 11 , 18 , 206 ]) or hemosiderin [ 203 , 207 ].…”

Section: Parametric T 2 -Relaxation Mappingmentioning

confidence: 99%

Current Methods of Magnetic Resonance for Noninvasive Assessment of Molecular Aspects of Pathoetiology in Multiple Sclerosis

Hnilicová

Štrbák

Kolísek

et al. 2020

IJMS

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Multiple sclerosis (MS) is an autoimmune disease with expanding axonal and neuronal degeneration in the central nervous system leading to motoric dysfunctions, psychical disability, and cognitive impairment during MS progression. The exact cascade of pathological processes (inflammation, demyelination, excitotoxicity, diffuse neuro-axonal degeneration, oxidative and metabolic stress, etc.) causing MS onset is still not fully understood, although several accompanying biomarkers are particularly suitable for the detection of early subclinical changes. Magnetic resonance (MR) methods are generally considered to be the most sensitive diagnostic tools. Their advantages include their noninvasive nature and their ability to image tissue in vivo. In particular, MR spectroscopy (proton 1H and phosphorus 31P MRS) is a powerful analytical tool for the detection and analysis of biomedically relevant metabolites, amino acids, and bioelements, and thus for providing information about neuro-axonal degradation, demyelination, reactive gliosis, mitochondrial and neurotransmitter failure, cellular energetic and membrane alternation, and the imbalance of magnesium homeostasis in specific tissues. Furthermore, the MR relaxometry-based detection of accumulated biogenic iron in the brain tissue is useful in disease evaluation. The early description and understanding of the developing pathological process might be critical for establishing clinically effective MS-modifying therapies.

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“…Here we propose a theory which advances the iron relaxivity model and provides in vivo iron relaxivity measurements for identifying different iron compounds in the brain. We take advantage of the fact that R1 and R2* are governed by different molecular and mesoscopic mechanisms [36][37][38] , and therefore each of them may have a distinct iron relaxivity in the presence of paramagnetic substances. Based on our theoretical framework ("In vivo iron relaxivity model" in Methods), the linear dependency of R1 on R2* can be described by the following equation:…”

Section: Resultsmentioning

confidence: 99%

Non-invasive assessment of normal and impaired iron homeostasis in living human brains

Filo

Shaharabani

Hanin

et al. 2022

Preprint

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Strict iron regulation is essential for normal brain function. The main iron compounds responsible for iron homeostasis, transferrin and ferritin, are distributed heterogeneously across the brain and are implicated in aging, neurodegenerative diseases and cancer. However, non-invasive discrimination between iron compounds, such as transferrin and ferritin, remains a challenge. We present a novel magnetic resonance imaging (MRI) technology for mapping of iron compounds in the living brain (the r1-r2* relaxivity). The specificity of the r1-r2* relaxivity to the presence of ferritin and transferrin is validated by both bottom-up and top-down approaches, incorporating in vitro, in vivo and ex vivo analyses. In vitro, our MRI approach reveals the distinct paramagnetic properties of ferritin and transferrin. In the in vivo human brain, we validate our approach against ex vivo iron compounds quantification and gene expression. Our approach predicts the transferrin-ferritin fraction across brain regions and in aging. It reveals brain tumors' iron homeostasis, and enhances the distinction between tumor tissue and non-pathological tissue without contrast agents. Therefore, our approach may allow for non-invasive research and diagnosis of iron homeostasis in living human brains.

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The influence of iron oxidation state on quantitative MRI parameters in post mortem human brain

Cited by 34 publications

References 60 publications

Mutation‐related magnetization‐transfer, not axon density, drives white matter differences in premanifest Huntington disease: Evidence from in vivo ultra‐strong gradient MRI

Mutation‐related magnetization‐transfer, not axon density, drives white matter differences in premanifest Huntington disease: Evidence from in vivo ultra‐strong gradient MRI

Current Methods of Magnetic Resonance for Noninvasive Assessment of Molecular Aspects of Pathoetiology in Multiple Sclerosis

Non-invasive assessment of normal and impaired iron homeostasis in living human brains

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